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Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene × environment interactions have been hypothesized to modulate several of these effects.

Introduction

Depressive disorders constitute a major public health issue and have been estimated to be the fourth major cause of disability worldwide, and may become second only to cardiovascular diseases in the next two decades (Mathers et al., 2000), thus contributing heavily to the global burden of diseases in man, according to Murray and Lopez (1997), who conducted a study for the World Health Organization (WHO). Unfortunately, depressed patients are not totally satisfied with the current effectiveness and tolerance of available antidepressant (AD) medications. Less than 50% of all patients treated with the currently available ADs show full remission and despite the clear need for better therapies, recent efforts to develop novel ADs have been relatively unsuccessful (Agid et al., 2007). The recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that even with systematic measurement-based treatment, approximately one-third of patients reach full remission after one treatment trial, with only two-thirds reaching remission after four treatment trials. Treatment-resistant depression (TRD) is therefore a common problem in the treatment of major depressive disorder (MDD), with 60–70% of all patients meeting the criteria for TRD (Rush et al., 2006a,b; Trivedi et al., 2006a,b). It becomes of great interest to the scientific community and to our patients to report, in future clinical trials, not response rates alone but also remission rates, in order to assess the real clinical AD efficacy. This is relevant in order to improve the still incomplete knowledge of the pathogenetic mechanisms of depression and to better understand the AD mechanisms of action, in order to develop new AD drugs with a better efficacy and safety profiles. ADs currently available include first- and second-generation drugs. First-generation ADs (FGAs) include monoamine oxidase inhibitors (MAOIs) and tricyclic ADs (TCAs), which became available for therapy in the 1960s. The mechanism of MAOIs and TCAs represented the main evidence for the monoamine hypothesis of depression and major depression (MD), an intrinsically tautological hypothesis which, nevertheless, has driven pharmacological research on depression for over four decades (Blier and de Montigny, 1994; Stahl, 1998). Second-generation ADs (SGAs) include several different classes of drugs that were developed mainly in the 1980s and 1990s, starting with selective serotonin reuptake inhibitors (SSRIs) and including serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NARIs), noradrenergic and specific serotonergic ADs (NaSSAs), and 5-hydroxytryptamine 2A (5-HT2A) receptor antagonists/reuptake inhibitors (SARIs). All the SGAs are based on the monoamine hypothesis, with a primary mechanism consisting of monoamine reuptake inhibition and/or antagonism for selected monoamine receptor(s) (Stahl, 1998). Finally, there is a class of third-generation drugs (TGAs), novel compounds that are in most cases characterized by non-monoaminergic mechanisms (although some of these have been in development for quite a while). Most of these compounds are based on peptidergic, glutamatergic, or circadian rhythm-related mechanisms, but a few still relate to a monoaminergic mechanism (Racagni and Popoli, 2008). Nowadays one of the more promising approaches in psychiatric research is pharmacogenetics. The aim of pharmacogenetics is to detect genetic factors that determine variations both in clinical response and in side effects under pharmacotherapy. It is well known that the large interpatient variability in clinical response to ADs is influenced by a variety of genetic as well as pathophysiological and environmental factors. The basis for such marked interindividual variations in the clinical response to AD treatments is not clear yet. However it seems that at least some of this variation has a genetic basis (Serretti et al., 2005a). Increasing evidence suggests that single nucleotide polymorphisms (SNPs) can be used in clinical association studies to determine the contribution of genetic variance in drugs response (Malhotra et al., 2004; Serretti et al., 2005a; Drago et al., 2009). In recent years, the development of pharmacogenetics has provided more opportunities for individualized pharmacotherapy of depressive disorders (Perlis, 2007; Horstmann and Binder, 2009). At present time, most pharmacogenetic studies investigated genes related to metabolism, genes coding for receptors and transporters and genes related to the second messenger system (Perlis, 2007). In this review, we summarize the major findings related to the pharmacogenetics of genes affecting response to ADs. To reach this target we reviewed the literature searching the MEDLINE and EMBASE (September 2010) using the search terms pharmacokinetics, pharmacodynamics, gene, variation, AD, efficacy, depression, mood disorder, genetic, candidate, cytochrome, P-glycoprotein (Pgp), tryptophan hydroxylase (TPH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A), HTT, norepinephrine transporter (NET), dopamine transporter (DAT), 5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, 5-HT6, angiotensin converting enzyme (ACE), circadian locomotor output cycles kaput protein (CLOCK), nitric oxide synthase (NOS), interleukin 1-beta (IL-1B), brain-derived neurotrophic factor (BDNF), glycogen synthase kinase 3 beta (GSK-3β), adrenoreceptor beta-1 (ADRB1), adrenoreceptor alpha-2 (ADRA2A), dopamine receptors, Gbeta3, corticotropin releasing hormone (CRH) receptor (CRHR1), glucocorticoid receptor (GR), glutamate receptor (also using extensive gene names; for overview see Table 1).

TABLE 1

Table 1. Overview of genetic association studies.

Pharmacokinetics

Cytochrome P450

Differences in AD plasma concentrations, and possibly safety, may be caused by polymorphisms in the genes that encode some of the cytochrome P450 (CYP) isoenzymes that metabolize ADs. The CYP superfamily is a class of proteins containing a heme cofactor that localize mainly to the liver. They represent the major enzymes responsible for the phase I oxidative reactions of many drugs and endogenous substances and over 50 isoenzymes are known so far (Ingelman-Sundberg et al., 2007). The most relevant cytochromes in humans are: CYP1A, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A.

The metabolic activity of CYPs is genetically determined and mutations or polymorphisms in genes coding for CYP isoforms can result in enzyme variants with higher, lower or no activity. As shown in Table 2, the isoenzymes CYP1A2, CYP2C9/19, CYP2D6, and CYP3A4 are the major enzymes that catalyze AD metabolic reactions (Spina et al., 2008).

With regards to CYP2D6 gene in particular, its polymorphisms were associated with the metabolism of most AD drugs (Lin and Lu, 1998). So far, more than 100 different alleles were reported at different frequencies in different populations of the world (for information see http://www./cypalleles.ki.se/), with a considerable number of variants which encodes inactive isoforms or with decreased or negligible activity, while other variations consist of gene duplications (Bertilsson et al., 2002). Those gene variants are often associated with different drug metabolism rate. According to the inherited CYP2D6 alleles, individuals are classified as poor (PM), intermediate (IM), extensive (EM), or ultrarapid (UM) metabolizers. Individuals who are PMs have a combination of two partially or totally defective alleles and often, they complain of side effects and drug intolerance at low dosages of drugs for its accumulation. Occasionally, these individuals are labeled as non-compliant for treatment. IMs have in their allelic combination one wild type allele plus one a partially or totally defective allele. The expected phenotype is between the EM and the PM phenotypes. In the case of CYP2D6, there is good evidence for a linear relationship between gene copy number and metabolism of a drug (i.e., amitriptyline and nortriptyline; Grasmader et al., 2004; Steimer et al., 2004). It is reasonable to expect that those drugs predominately metabolized through CYP2D6 may also show an IM status due to the low hepatic content of CYP2D6 and limiting enzymatic capacity. Drugs with additional metabolic routes (i.e., CYP2C19 and CYP3A) may have IM or EM status due to the additional metabolic routes for drug elimination. Individuals who are EM, also called normal or “wild type” have two active alleles. This genotype serves as the reference genotype for other studies. The UM category exists for CYP2D6 and CYP1A2 enzymes. UM individuals usually have multiple copies of the allele on one or the other chromosome, this condition increased enzymatic activity due to an increased the amount of protein produced (Gaikovitch et al., 2003). Interesting and noteworthy the prevalence of different genotypes and phenotypes is notably different depending on ethnicity.

Pharmacogenetic studies which investigated the influence of CYP2D6 variants on AD outcome actually do not reach univocal results; this may at least partly be due to the heterogeneity of studied populations. Indeed, while some authors reported positive association with therapeutic effects (Rau et al., 2004; Tsai et al., 2010) or side effects (Rau et al., 2004; Shams et al., 2006; Suzuki et al., 2006), other authors found lack of association (Murphy Jr. et al., 2003; Grasmader et al., 2004; Serretti et al., 2009; Murata et al., 2010), both for therapeutic and side effects (Peters et al., 2008). Moreover, several authors found an association between CYP2D6 variants and AD serum levels (Charlier et al., 2003; Grasmader et al., 2004; Suzuki et al., 2010; Tsai et al., 2010), but without univocal results (Murphy Jr. et al., 2003; Ohara et al., 2003). In the case of CYP1A2, duplications do not occur, but polymorphisms affecting transcription and translation of the encoded protein in the presence of inducers, such as tobacco smoke, can produce a UM phenotype (Sachse et al., 1999; Pavanello et al., 2005). UMs often requires doses of a CYP2D6-metabolized drug above (e.g., fluoxetine) or below (e.g., codeine, which is a prodrug for morphine) than conventional dosing guidelines to achieve a therapeutic desired effect. The CYP2C19 gene is on another cytochrome gene active in the metabolism of several ADs (Liu et al., 2002b; Yin et al., 2006; Rudberg et al., 2008; Schenk et al., 2010), and largely investigated concerning AD response. Also in this case the different isoforms of the gene allowed a classification in phenotypes, with a group of subjects labeled as EM, another one with impaired catalytic capacity, called PM (Smith et al., 1998a,b); and an UM group (Rudberg et al., 2008). In conclusion, the pharmacokinetics of ADs is significantly altered, in particular by CYP2D6 and more marginally by CYP2C19 polymorphisms. However, it is still controversial whether therapeutic efficacy may be improved and/or adverse effects could be prevented by the use of genotyping procedures, particular considering that genotype often do not correspond to a well-defined phenotype as state above. With regard to this, the recent approval by the FDA of the pharmacogenetic test, the AmpliCyp CYP450 Test (Roche Molecular System Inc.), assessing both polymorphic genes CYP2D6 and CYP2C19, may be of help to validate studies on personalized therapy of depression.

Monoamine oxidase A

Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. In humans there are two types of MAO: MAO-A and MAO-B, and both are found in CNS, in particular in neurons and astroglia. The MAO-A, coded by the MAO-A gene, metabolizes several important amines and catecholamines including dopamine, serotonin, and NE. Polymorphism in the gene’s promoter region is due to a repetitive sequence [variable number tandem repeat (VNTR)] located 1.2 kb upstream of the MAO-A gene, regulates the activity of the MAO-A gene and have been linked to variations in the biological activity and also influences the concentration of serotonin (Sabol et al., 1998). Because the activity of MAO-A influences neurotransmitter concentrations, polymorphisms in these genes may affect AD response. Researchers like Tadic et al. (2007) and more recently Tzeng et al. (2009) reported that the VNTR polymorphism in the MAO-A gene promoter region was associated with mirtazapine response. Nevertheless, as a matter of fact, several reports did not found any correlation between this polymorphism and the AD response (Cusin et al., 2002; Muller et al., 2002; Yoshida et al., 2002; Peters et al., 2004). Other polymorphisms within this gene were more marginally studied, with some positive but not replicated results. Particularly Peters et al. (2004) reported an association between rs1465108 and rs6323 and fluoxetine response whilst Tadic et al. (2007) found an association between rs1799835 and mirtazapine response only in the female sample). Finally an effect of the rs6323 genotype on the placebo response has been reported (Leuchter et al., 2009).

Norepinephrine transporter (SLC6A2)

The norepinephrine transporter or NET [or noradrenaline transporter (NAT)] is encoded by the SLC6A2 gene. It is a monoamine transporter that transports the neurotransmitters NE (noradrenaline) from the synapse back to cytosol, hence other transporters vesicular monoamine transporter (VMAT) sequester NE into vesicles for later storage and release. Several investigators have studied the relationship between NET genetic polymorphisms and susceptibility to psychiatric disorders, including MD, bipolar disorder, schizophrenia, and alcohol dependence (Owen et al., 1999; Leszczynska-Rodziewicz et al., 2002; Samochowiec et al., 2002; Zill et al., 2002), without observing major findings. Several genetic variants are known in the human NET gene: rs5566 (A369P), rs5563 (N292T), rs5558 (F528C), rs5569 (G1287A), and rs2242446 (T-182C) variants were proved to be functional and impact the AD effect (Yoshida et al., 2004; Hahn et al., 2005; Kim et al., 2006). With particular regard to AD response, rs5569, a silent mutation is associated with the cerebrospinal fluid concentration of 3-methoxy-4-hydroxyphenylglycol, a major NE metabolite (Jonsson et al., 1998), and with the response to methylphenidate, a drug with noradrenergic action, in attention deficit hyperactivity disorder (ADHD; (Yang et al., 2004). The association between this polymorphism and the AD response was previously examined in Japanese patients by Yoshida et al. (2004): they reported that the NET G1287A polymorphism (A/A genotype) was associated with the onset of response but not the final clinical improvement. Moreover, Kim et al. (2006) showed a positive association between G/G rs5569 genotype and better response to nortriptyline, although no effect on SSRIs response has been detected. The NET T-182C polymorphism was first reported by Zill et al. (2002) and the presence of the T allele was associated with a superior response to milnacipran (Yoshida et al., 2004; for a review see Higuchi, 2010). Consistently one other study did not find any association between these polymorphisms and SSRIs (fluoxetine, paroxetine, or citalopram) or venlafaxine response in an Asiatic sample of depressed patients (Min et al., 2009). Recently other NET polymorphisms have been investigated: Uher et al. (2009) showed an association between rs60329 and rs1532701 polymorphism and favorable response to treatment with nortriptyline, and Dong et al. (2009) found that the rs5564 and rs1362621 were associated with remission with desipramine and fluoxetine treatment. Nevertheless, Baffa et al., 2010)did not found any association with seven polymorphisms in the promoter, intronic and exonic region of NET (rs35915, rs28386840, rs168924, rs2242446, rs36017, rs47958, rs171798). However, results are not unequivocal, and replication studies are warranted.

5-HT3A, 3B receptors

The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions; it is the only ion channel subtype in the serotonin family. Five different subunits, A–E, of the 5-HT3 receptor have been identified. Association studies have been carried out to establish causal relationships between genetic variants within genes encoding 5-HT3A and 5-HT3B and side effects profile rather than clinical response. Yamada et al. (2006) showed an association between haplotype block in the 5-HT3B gene [that includes Y129S (rs1176744) polymorphism] and MD in women and in patients with bipolar affective disorder (Frank et al., 2004). Likewise, a common variation in the regulatory region of the 5-HT3A gene C178T has been associated with bipolar affective disorder in Caucasians (Niesler et al., 2001), although a recent study on Japanese patients did not confirm this result (Yamada et al., 2006). Consistently HTR3A rs1062613 (C178T) and two polymorphisms in HTR3B (−100 −102 AAG deletion variant and rs1176744) have been found to be associated with chemotherapy and paroxetine treatment induced vomiting and nausea (Tremblay et al., 2003; Kato et al., 2006; Sugai et al., 2006; Tanaka et al., 2008). Nevertheless, studies on gastrointestinal side effects during SSRIs treatment showed no association with HTR3B rs1176744 (Suzuki et al., 2006; Tanaka et al., 2008), HTR3A rs1062613 and C195T (Sugai et al., 2006), as well as no association has been found between HTR3A (rs1062613) and HTR3B (rs35312182 and rs1176744) polymorphisms and paroxetine discontinuation syndrome (Murata et al., 2010).

5-HT6 receptor

The 5-HT6 receptor is a G protein-coupled receptor which is expressed almost exclusively in the brain. Genetic variants within this gene likely have an effect on brain and several studies have investigated whether 5-HT6 polymorphisms are associated with brain-related variables, such as neuropsychiatric disorders. In this regard, several studies showed an implication of this gene in some behavior trait (Ballaz et al., 2007; Mitchell et al., 2007). Moreover, it seems to be involved in AD mechanism (Svenningsson et al., 2007; Wesolowska and Nikiforuk, 2007). The C267T variant (rs1805054), in the first exon, may has a role in the modulation of AD response as well (Kohen et al., 1996; Lee et al., 2005). Indeed, this polymorphism (rs1805054) has been investigated for association with AD response in several studies. Despite preliminary negative results (Wu et al., 2001), a subsequent study reported that C/T carriers showed better AD response (Lee et al., 2005). Nevertheless, this finding has not been replicated by further studies (Illi et al., 2009; Wilkie et al., 2009).

Adrenoreceptor beta-1 and adrenoreceptor alpha-2

The ADRB1 and ADRA2A are G protein associated receptor: ADRB1 stimulates adenylate cyclase while alpha 2 adrenoreceptor inactivates adenylate cyclase. A recently identified functional polymorphism in the ADRB1 G(1165)C leading to the amino acid variation Gly389Arg may play a functional role, and it was associated with an enhanced coupling to the stimulatory Gs protein and increased adenylate cyclase activation, resulting in a better and faster response to AD treatment (Zill et al., 2003). Nevertheless, Crowley et al. (2008) failed to confirm the relevance of this gene in modulating the response to citalopram treatment. ADRA2A gene, it seems to be relate to the pretreatment hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and increased adrenocorticotropin in male depressed patients (Haefner et al., 2008). Recently, Perroud et al. (2009) showed an association between rs11195419 ADRA2A polymorphism and suicidality ideation among nortriptyline treated patients.

Dopamine receptors

Dopamine receptors are divided into D1-like family (D1 and D5, which are coupled to a Gs protein and activate adenylate cyclase), and D2-like family (D2, D3, and D4, which are coupled to a Gi protein and inhibit adenylate cyclase). Only the D2-like family was associated to depressive disorder. Focusing on AD response, we have some line of evidence suggesting a role for D2 receptor as well (Maj et al., 1989; Dziedzicka-Wasylewska and Solich, 2004; Willner et al., 2005). A functional polymorphism (S311C, rs1801028) within D2 receptor gene has been repeatedly investigated without finding any influence on AD response (Serretti et al., 2001a, 2004b; Benedetti et al., 2003b). However, a recent study showed an association between D2 rs4245147 SNP and lamotrigine response in a sample of bipolar depressed patients (Perlis et al., 2010), suggesting a role of this gene in AD response as well. In the same study (Perlis et al., 2010) founded an association between three D3 receptor SNPs (rs167770, rs6280, and rs2134655) and olanzapine/fluoxetine combination response in a sample of bipolar I depressed patients. Moreover, they reported a marginal association between D4 receptor SNP rs936461 and lamotrigine response (Perlis et al., 2010). Several studies investigated VNTR polymorphism in exon 3 of D4 receptor gene, in relationship with AD response, unfortunately with negative results (Serretti et al., 1999, 2001a), except for Garriock et al. (2006)who found a significant modulation effect on various AD medications.

Glucocorticoid receptor

Hyperactivity of HPA axis might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the GR (or NR3C1). Within this gene several polymorphisms have been associated with MDD and AD response. In particular, the BclI and ER22/23EK polymorphisms were associated with susceptibility to develop MD (van Rossum et al., 2006). In addition, the ER22/23EK polymorphism was associated with a faster clinical response to AD treatment (van Rossum et al., 2006). Recently, these results were not repeated in Korean depressive patients (Lee et al., 2009). Brouwer et al. (2006) found that carriers of the BcII polymorphism have higher baseline ATCH values and they showed a trend toward lower decrease of Hamilton Rating Scale for Depression rates than non-carriers. Finally, the rs852977, rs10482633, rs10052957 polymorphisms were associated with AD response in the STAR?D sample, although none of them survived after correction for hypothesis-wide effective number of comparisons (Uher et al., 2009).

c-AMP Response-Element Binding

An increasing number of studies recently focused on the role of the c-AMP response-element binding (CREB) protein in MDD. As a matter of fact, several studies found a role of CREB both in the etiology and pharmacotherapy of MDD (Sulser, 2002; Blendy, 2006). CREB1 has also been found to be associated with AD response in depressed patients (Wilkie et al., 2007) and with lithium response in patients with bipolar disorder (CREB1-1H and CREB1-7H SNPs; Mamdani et al., 2008). Further, rs4675690, a SNP located at the 5′ of CREB1, was found to have a role in suicidal behaviors in patients with MD (Perlis et al., 2007b) and, along with rs7569963, to be associated with anger expression in men suffering from MD (Perlis et al., 2007a). Despite some negative results (Burcescu et al., 2005; Hettema et al., 2009), current evidence suggests that CREB1 could play an important role both in the development of MDD and related features as well as in the ADs response like showed in several studies on animal models (Thome et al., 2000; Kuipers et al., 2006; Tardito et al., 2006; Boer et al., 2010). The CREB1 polymorphisms are still poorly investigated in the field of pharmacogenetic of AD response, resistance and remission. Dong et al. (2009), like Wilkie et al. (2007), failed to find any association between several CREB polymorphisms and AD response, although they showed a significant association between one SNP (rs3730276) and MDD. Recently, Serretti et al. (2011) suggested that some alleles or haplotypes within CREB1 could be related to treatment resistance but not to response and remission to current AD treatment as well as to a diagnosis of MD. Finally, Perlis et al. (2007a) suggested a role of genetic variants within CREB gene on treatment-emergent suicidal ideation during citalopram treatment. Interestingly they found significant associations only in men, suggesting a significant gene × sex interaction.

Genome-Wide Association Studies

A genome-wide association study (GWAS) is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. This innovative method seems particularly useful to study complex diseases, such as psychiatric disorders. One of the limits of this methodology is the risk of false positive results. Even if in AD pharmacogenetics, the number of GWAS performed is limited and results need replication, unbiased approaches using genome-wide gene expression or association results could lead to important advances in this field. Recently, GWAS were performed within the GENDEP project and the STAR*D (Craddock et al., 2009; Garriock and Hamilton, 2009; Ising et al., 2009; Laje et al., 2009; Perroud et al., 2010). One of the major limits of GWAS is the incapacity to detect rare genetic variants (<1% of the population). Indeed, current GWAS technologies are able to detect only association for genetic variants present in 5% or more of the population (Craddock et al., 2009). The results reached by GWAS, to date, have been disappointing. For this reason large meta-analysis to reach genome-wide significance are often needed (McCarthy and Hirschhorn, 2008).

Conclusion

The synopsis of pharmacogenetic studies indicates several strong candidate genes involved in AD response. Nonetheless, the lack of standardized study design renders meta-analyses as well as comparisons across studies difficult. Several factors can influence the results that often are conflicting: inclusion criteria, medication, outcome and side effect measures, ethnicity, and genetic coverage. Given the complex nature of the biology of AD treatment response and the relevance of environmental factors, such as repeated treatment, number of episodes or the occurrence of life events, the addition of non-genetic markers for optimal treatment prediction will likely be necessary (Holsboer, 2008). There is great hope that the field of pharmacogenomics will offer personalized medicine treatments based on genetic profiles and in this way may have the potential to offer many benefits for further therapeutic approaches.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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